DRUG INTERACTIONS

 Sensitive CYP3A4 Substrates:                                                                                     Avoid co-administration of sensitive CYP3A4 substrates with a narrow therapeutic index 

 Strong CYP3A4 Inhibitors or Fluconazole:                                                                   Avoid co-administration with strong CYP3A4 inhibitors or fluconazole. If unavoidable, reduce the dose of OXBRYTA 

 Strong or Moderate CYP3A4 Inducers:                                                                          Avoid co-administration with strong or moderate CYP3A4 inducers. If unavoidable, increase the dose of OXBRYTA 

 WARNINGS-

 Hypersensitivity Reactions:                                                                                     Observe for signs and symptoms and manage promptly 

Laboratory Test Interference:                                                                                    Perform quantification of hemoglobin species when patient is not receiving the drug

 ADVERSE REACTIONS

 Most common adverse reactions (incidence >10%) are headache, diarrhea, abdominal pain, nausea, fatigue, rash, and pyrexia 

 WARNINGS AND PRECAUTIONS

 Hypersensitivity Reactions:                                                                                     Observe for signs and symptoms and manage promptly (

Laboratory Test Interference:                                                                                    Perform quantification of hemoglobin species when patient is not receiving OXBRYTA (5

 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Advise patients that serious hypersensitivity reactions may occur, and to notify their healthcare providers if they develop generalized rash, urticaria, shortness of breath, facial swelling and eosinophilia [

Advise women not to breastfeed while they are on OXBRYTA therapy 

Advise patients to:  Continue taking OXBRYTA every day for as long as their physician tells them.

1.This is a long-term treatment.                                                                                   2.Swallow OXBRYTA tablets whole.                                                                                     3.Do not cut, crush, or chew the tablets.                                                                             4. Take with or without food.                                                                                                 5. If a dose is missed, continue dosing on the day following the missed dose 

Global Blood Therapeutics, Inc. at 1-833-428-4968 (1-833-GBT-4YOU).

 CLINICAL PHARMACOLOGY 

1. Mechanism of Action                                                                                       Voxelotor is a hemoglobin S (HbS) polymerization inhibitor that binds to HbS with a 1:1 stoichiometry and exhibits preferential partitioning to red blood cells (RBCs).

By increasing the affinity of Hb for oxygen, voxelotor demonstrates dose-dependent inhibition of HbS polymerization. Nonclinical studies suggest that voxelotor may inhibit RBC sickling, improve RBC deformability, and reduce whole blood viscosity.

2. Pharmacodynamics                                                                                                    The pharmacodynamic effect of voxelotor treatment demonstrated a dose-dependent increase in Hb oxygen affinity as determined by the change in p50 (partial pressure of oxygen at which Hb oxygen saturation of 50% is achieved) that was linearly correlated with voxelotor exposure.

Cardiac Electrophysiology                                                                                             At plasma concentrations approximately 2-fold above therapeutic concentrations, voxelotor does not prolong QT interval to any clinically relevant extent.

3. Pharmacokinetics                                                                                               Voxelotor is absorbed into plasma and is then distributed predominantly into RBCs due to its preferential binding to Hb.

The major route of elimination of voxelotor is by metabolism with subsequent excretion of metabolites into urine and feces. The PK are linear and voxelotor exposures increased proportionally with either single or multiple doses  in whole blood, plasma, and RBCs.

Steady-state after repeated administration is reached within 8 days and exposures of voxelotor are consistent with accumulation predicted based on single dose data in patients with SCD.

 Pharmacokinetics -Parameters of Voxelotor in Plasma and Whole Blood PK Parameter Voxelotor 1,500 mg Geometric Mean (%CV) Plasma PK AUC0-24h (µg?hr/mL) 246 (27.7) Cmax (µg/mL) 12.6 (24.8) Half-life (hours) 35.5 (25) Whole Blood PK AUC0-24h (µg?hr/mL) 3820 (35) Cmax (µg/mL) 179 (33.1)

Absorption                                                                                                                     The median plasma and whole blood Tmax of voxelotor after oral administration is 2 hours. The mean peak concentrations in whole blood and RBCs are observed between 6 and 18 hours after oral administration.

Effect of Food                                                                                                                   A high-fat, high-calorie meal increased voxelotor AUC by 42% and Cmax by 45% in whole blood relative to AUC and Cmax in the fasted state. Similarly, AUC increased by 42% and Cmax increased by 95% in plasma.

Distribution                                                                                                                   Voxelotor apparent volume of distribution of the central compartment and peripheral compartment are 338 L and 72.2 L in plasma, respectively. Protein binding is 99.8% in vitro. The blood-to-plasma ratio is approximately 15:1 in patients with SCD.

Elimination                                                                                                                       The geometric mean (%CV) terminal elimination half-life of voxelotor in patients with SCD is 35.5 hours (25%) with concentrations in plasma, whole blood, and RBCs declining in parallel. The apparent oral clearance of voxelotor was estimated as 6.7 L/h in plasma in patients with SCD.

Metabolism                                                                                                                       In vitro and in vivo studies indicate that voxelotor is extensively metabolized through Phase I (oxidation and reduction), Phase II (glucuronidation) and combinations of Phase I and II metabolism. Oxidation of voxelotor is mediated primarily by CYP3A4, with minor contribution from CYP2C19, CYP2B6, and CYP2C9.

Excretion                                                                                                                  Following the administration of radiolabeled voxelotor, approximately 62.6% of the dose and its metabolites are excreted into feces (33.3% unchanged) and 35.5% in urine (0.08% unchanged).

Specific Populations                                                                                                      No clinically significant differences in the pharmacokinetics of voxelotor were observed based on age (12 to 59 years), sex, body weight (28 to 135 kg), or mild to severe renal impairment (creatinine clearance [CLcr] 15-89 mL/min).

Pediatric Patients                                                                                                                 The pharmacokinetic parameters of voxelotor were similar in pediatric patients 12 to <17 years and adults.

Patients with Renal Impairment                                                                                There was no clinically significant effect of renal function on the excretion of voxelotor. Following a single 900 mg dose of voxelotor, whole blood exposures in subjects with severe renal impairment (eGFR <30 mL/min/1.73 m2 ) were 25% lower compared to healthy controls. 

The unbound plasma concentrations were comparable. OXBRYTA has not been evaluated in patients with end stage renal disease requiring dialysis.

Patients with Hepatic Impairment                                                                                   The voxelotor AUC in whole blood were 14% and 15% higher in subjects with mild and moderate hepatic impairment (Child Pugh A and B) and 90% higher in subjects with severe hepatic impairment (Child Pugh C) compared to subjects with normal hepatic function.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches                                                       

Effect of Strong CYP3A4 Inhibitors on Voxelotor:                                         concomitant use of OXBRYTA with ketoconazole is predicted to increase voxelotor AUC in patients by 42% to 83%.

Effect of Strong or Moderate CYP3A4 Inducers on Voxelotor:                                     concomitant use of OXBRYTA with rifampin (a strong CYP3A4 inducer) is predicted to decrease voxelotor AUC in patients by up to 77%, and efavirenz (a moderate CYP3A4 inducer) is predicted to decrease voxelotor AUC in patients by up to 60%.

Effect of Fluconazole on Voxelotor:                                                                         concomitant use of OXBRYTA with fluconazole, a moderate CYP3A4 inhibitor, a moderate CYP2C9 inhibitor and a strong CYP2C19 inhibitor, is predicted to increase voxelotor AUC in patients by 40% to 116%.

Effect of Acid Reducing Agents on Voxelotor:                                                                  co-administration of omeprazole (proton pump inhibitor) with OXBRYTA did not alter voxelotor exposure.

Effect of Voxelotor on CYP450 Enzymes:                                                                         in vivo voxelotor inhibits CYP3A4, but not CYP1A2, CYP2C9, CYP2C19, CYP2C8, or CYP2D6. The observed exposure increase of the CYP3A4 substrate midazolam in healthy subjects was 1.6-fold and the predicted increase in patients after multiple dosing is 2-fold.

Effect of Voxelotor on P-gp: concomitant use of OXBRYTA with digoxin                     (a P-gp substrate) did not alter digoxin to a clinically relevant extent. In Vitro Studies CYP Enzymes: voxelotor is a reversible and time-dependent inhibitor as well as an inducer of CYP2B6.

Transporter Systems: voxelotor is not an inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, MATE2-K, or BSEP. Voxelotor is not a substrate of P-gp, BCRP, OATP1A2, OATP1B1, OATP1B3, or BSEP. 10 Reference ID: 4517492

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary                                                                                               There are no available data on OXBRYTA use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. 

The estimated background risk of major birth defects and miscarriage for the indicated population is approximately 14% and up to 43%, respectively.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 

There are adverse effects on maternal and fetal outcomes associated with sickle cell disease in pregnancy (see Clinical Considerations). OXBRYTA should only be used during pregnancy if the benefit of the drug outweighs the potential risk.

Clinical Considerations                                                                                              Disease-Associated Maternal and/or Embryo/Fetal Risk                                          Women with sickle cell disease have an increased risk of adverse pregnancy outcomes for the mother and the fetus.

Pregnant women are at greater risk for vasoocclusive crises, pre-eclampsia, eclampsia, and maternal mortality. For the fetus, there is an increased risk for intrauterine growth restriction, preterm delivery, low birth weight, and perinatal mortality. 

2. Lactation Risk Summary                                                                                         There are no data on the presence of voxelotor in human milk, the effects on the breastfed child, or the effects on milk production. Voxelotor was detected in milk in lactating rats. 

Because of the potential for serious adverse reactions in the breastfed child, including changes in the hematopoietic system, advise patients that breastfeeding is not recommended during treatment with OXBRYTA, and for at least 2 weeks after the last dose.

3.Pediatric Use                                                                                                              The safety and effectiveness of OXBRYTA for sickle cell disease have been established in pediatric patients aged 12 years and older. Use of OXBRYTA for sickle cell disease is supported by evidence from an adequate and well-controlled study in adults and pediatric patients (HOPE trial).

4.Geriatric Use                                                                                                                Clinical studies of OXBRYTA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

5.Hepatic Impairment                                                                                                Severe hepatic impairment increases voxelotor exposures